Stereoselective olefin isomerization leading to asymmetric quaternary carbon construction

Article abstract of DOI:10.1021/ol0706511

Chemo- and stereoselective Ir(I)-catalyzed isomerization of 1,1-disubstituted and trisubstituted allylic ethers and in situ [3,3] sigmatropic rearrangement of the resulting allyl vinyl ethers provide for the highly stereoselective construction of quaterna

Full text of DOI:10.1021/ol0706511

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2325-2328
Stereoselective Olefin Isomerization
Leading to Asymmetric Quaternary
Carbon Construction
Kan Wang, Christopher J. Bungard, and Scott G. Nelson*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
sgnelson@pitt.edu
Received March 21, 2007
ABSTRACT
Chemo- and stereoselective Ir(I)-catalyzed isomerization of 1,1-disubstituted and trisubstituted allylic ethers and in situ [3,3] sigmatropic
rearrangement of the resulting allyl vinyl ethers provide for the highly stereoselective construction of quaternary carbon stereocenters. The
olefin isomerization−Claisen rearrangement (ICR) sequence allows adjacent quaternary−tertiary stereocenter relationships to be established
with excellent diastereoselection. Several complementary strategies for enantioselective quaternary carbon synthesis derive directly from the
ICR reaction design.
Asymmetric construction of quaternary carbon stereocenters
continues to pose a special challenge in organic synthesis.1
[3,3] Sigmatropic rearrangements are among the well-
established methods affording general access to all-carbon
stereocenters even in architecturally complex settings.2,3
Ireland enolate-Claisen rearrangements, the most versatile
and widely utilized variant of the [3,3] sigmatropic re-
arrangements, therefore provide an especially attractive
strategy for introducing sterically congested quaternary
carbon stereocenters.4,5 However, extending the Ireland-
Claisen methodology to acyclic substrates is complicated by
the poor control of enolate geometry accompanying eno-
lization of R-disubstituted esters and the resulting errosion
of Claisen diastereoselection (Figure 1).6 This analysis led
us to examine olefin isomerization-Claisen rearrangement
(ICR) reactions as a strategy for achieving asymmetric
(1) Recent reviews: (a) Denissova, I.; Barriault, L. Tetrahedron 2003,
59, 10105-10146. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363-5367. (c) Quaternary Stereocenters; Christ-
offers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, 2005. (d) Trost, B. M.;
Jiang, C. Synthesis 2006, 369-396.
(4) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897-
5898.
(5) Chelate-organized and/or cyclic enolates can provide good control
of enolate geometry for R,R-disubstituted esters in advance of Ireland-
Claisen rearrangements. (a) For a review, see ref 1c, pp 120-131. For other
selected examples, see: (b) Ireland, R. E.; Wipf, P.; Armstrong, J. D., III
J. Org. Chem. 1991, 56, 650-657. (c) Echavarren, A. M.; de Mendoza, J.;
Prados, P.; Zapata, A. Tetrahedron Lett. 1991, 32, 6421-6424. (d) Devine,
P. N.; Meyers, A. I. J. Am. Chem. Soc. 1994, 116, 2633-2634. (e) Gilbert,
J. C.; Selliah, R. D. Tetrahedron 1994, 50, 1651-1664. (f) Enders, D.;
Knopp, M. Tetrahedron 1996, 52, 5805-5818. (g) Calad, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2005, 127, 2046-2047.
(2) Ziegler, F. E. Chem. ReV. 1988, 88, 1423-1452 and references
therein.
(3) For selected examples: (a) Ziegler, F. E.; Klein, S. I.; Pati, U. K.;
Wang, T.-F. J. Am. Chem. Soc. 1985, 107, 2730-2737. (b) Ziegler, F. E.;
Nangia, A.; Schulte, G. J. Am. Chem. Soc. 1987, 109, 3987-3991. (c)
Lemieux, R. N.; Meyers, A. I. J. Am. Chem. Soc. 1998, 120, 5453-5457.
(d) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388-
401. (e) Boeckman, R. K., Jr.; del Rosario Rico Ferreira, M.; Mitchell, L.
H.; Shao, P. J. Am. Chem. Soc. 2002, 124, 190-191.
10.1021/ol0706511 CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/17/2007

isomerization and Claisen stereoselectivity. Reacting 1 with
2 mol % of Ir(PCy3)3BPh4 (3) at 75 °C elicited highly
Z-selective isomerization and concomitant sigmatropic re-
arrangement to directly generate the 2,2-disubstituted pen-
tenal derivative anti-4 (anti/syn ) 97:3, 60%) (Figure 2).
Figure 1. ICR-based strategy for quaternary carbon construction.
Claisen-based chiral quaternary carbon construction that
would share the operational simplicity and reliability char-
acterizing the Ireland-Claisen process.7,8 This account
describes the highly stereoselective construction of quaternary
carbon stereocenters via chemo- and stereoselective Ir(I)-
catalyzed isomerization of 1,1-disubstituted and trisubstituted
allylic ethers and in situ [3,3] sigmatropic rearrangement of
the resulting allyl vinyl ethers. These investigations reveal
several complementary strategies for the enantioselective
construction of all-carbon quaternary stereocenters based on
the ICR technology.
Achieving rigorous stereocontrol in the ICR-based Claisen
rearrangements is predicated on controlling vinyl ether
geometry during the initial olefin isomerization event. During
isomerization of 1,1-disubstituted or trisubstituted allyl ethers,
the limited energetic differentiation of the resulting E- or
Z-vinyl ethers raises concerns for controlling olefin geometry
and, ultimately, Claisen stereoselectivity. As a result, docu-
menting the capacity of metal-catalyzed isomerization of 1,1-
disubstituted or trisubstituted allylic ethers to deliver stereo-
defined trisubstituted vinyl ethers was an essential component
of these investigations. Moreover, enantioselective reaction
variants would be predicated on the 2,2-disubstituted vinyl
ether moieties causing limited disruption of chairlike transi-
tion states responsible for efficient transfer of substrate
chirality during bond reorganization.
Figure 2. Correlating ICR substrate regiochemistry and Claisen
diastereoselectivity.
The trisubstituted allyl ether 2 participated in similarly
stereoselective ICR reorganization to provide the syn-2,2,3-
trisubstituted pentenal syn-4 in 66% yield (syn/anti )
95:5). These preliminary investigations suggested that oxida-
tive insertion at allylic C-H bonds other than those adjacent
to oxygen was not operative in these reactions. Thus, the
regioisomeric di(allyl) ethers 1 and 2 are not subject to Ir-
(I)-catalyzed interconversion prior to vinyl ether formation,
and once generated, the unique vinyl ether isomers 5 and 6
are immune to scrambling of olefin geometry that would
accompany random allylic C-H insertion. This observation
correlates olefin regiochemistry, rather than olefin stereo-
chemistry, with the stereochemical outcome of the [3,3]
sigmatropic rearrangement.
Analyzing the data presented in Table 1 reveals the general
access to quaternary carbon stereocenters afforded by the
ICR methodology. A variety of 1,1-disubstituted allylic ethers
(e.g., 7) possessing aliphatic alkyl, branched alkyl, and
protected oxygen substituents undergo highly diastereo-
selective ICR reorganization to generate the stereodefined
R,R-disubstituted pentenals 8a-e (dr ) 97:3-87:13) (entries
a-e).9 Claisen rearrangement of the benzyl-substituted allylic
ethers 7c and 7d serves to highlight that olefin isomerization
is highly regioselective even when resonance-stabilized
styrene formation is a possible competing pathway. Trisub-
stituted allyl ethers 7g and 7h also afford efficient conduits
to all-carbon stereocenters, delivering Claisen adducts 8g and
8h with excellent syn stereocontrol of the vicinal quaternary-
Preliminary efforts addressing these issues employed ethers
1 and 2 as representative test substrates for assaying olefin
(6) Selected recent examples of stereoselective quaternary carbon
construction via [3,3] sigmatropic rearrangement of allyl vinyl ethers: (a)
May, J. H.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426-12427. (b)
Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978-4979.
(c) Miyamoto, H.; Okawa, Y.; Nakazaki, A.; Kobayashi, S. Angew. Chem.,
Int. Ed. 2006, 45, 2274-2277.
(7) (a) Nelson, S. G.; Bungard, C. J.; Wang, K. J. Am. Chem. Soc. 2003,
125, 13000-13001. (b) Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006,
128, 4232-4233.
(8) Other examples of olefin isomerization-Claisen rearrangements: (a)
Reuter, J. M.; Salomon, R. G. J. Org. Chem. 1977, 42, 3360-3364. (b)
Wille, A.; Tomm, S.; Frauenrath, H. Synthesis 1998, 305-308. (c)
Higashino, T.; Sakaguchi, S.; Ishii, Y. Org. Lett. 2000, 2, 4193-4195. (d)
Ben Ammar, H.; Le Noˆtre, J.; Salem, M.; Kaddachi, M. T.; Dixneuf, P. H.
J. Organomet. Chem. 2002, 662, 63-69. (e) Le Noˆtre, J.; Brissieux, L.;
Se´meril, D.; Bruneau, C.; Dixneuf, P. H. Chem. Commun. 2002, 1772-
1773. (f) Schmidt, B. Synlett 2004, 1541-1544. (g) Nevado, C.; Echavarren,
A. M. Tetrahedron 2004, 60, 9735-9744.
(9) The relative stereochemistry for 8a was established by X-ray
diffraction analysis of the corresponding semicarbazide derivative; data are
provided in the Supporting Information.
2326
Org. Lett., Vol. 9, No. 12, 2007

Table 1. Olefin Isomerization-Claisen Rearrangement of
1,1-Disubstituted and Trisubstituted Allyl Ethersa-c
Figure 3. Mechanism for olefin isomerization stereoselectivity.
between the ether and the Ir(III)-phosphine moieties results
in reductive elimination proceeding via 9 to selectively
generate E- or Z-enol ethers from 1,1-disubstituted or
trisubstituted allyl ethers, respectively.
Among the defining characteristics of these ICR reactions
is the flexibility they offer in devising enantioselective
reaction variants. First, enantioenriched ICR substrates were
prepared in a single step by catalytic asymmetric Et2Zn-
aldehyde addition and in situ zinc alkoxide allylation under
Pd(0) catalysis (eq 1).10 Under the ICR reaction conditions,
the enantioenriched 1,1-disubstituted allylic ethers 7d/e
afforded the 2,2-disubstituted-4-pentenals 8d and 8e with
near perfect chirality transfer. Alternatively, enantioenriched
ICR substrates could be prepared by asymmetric aldehyde
allylation followed by O-alkylation (81% ee) (eq 2).11,12 Allyl
1
a Diastereomer ratios (dr) determined by 500 MHz H NMR or HPLC
analysis. bProduct enantiomeric purity reported in parentheses for reactions
c
employing enantioenriched di(allyl) ethers 7. Percentage of zC4-C5 olefin
isomer in parentheses.
tertiary stereocenter relationships. Certain substrates bearing
aliphatic C2 alkyl substituents can yield minor amounts of
the C4-C5 cis-olefin isomer (Table 1, entry c); quenching
the Ir(I) catalyst (3 mol % of PPh3) prior to thermolysis
prevents post-rearrangement olefin isomerization (entries d
and e).7a
Vinyl ether stereochemistry is dictated by the energetic
differentiation of the η1 organoiridium species 9 and 10 that
immediately precede vinyl ether formation (Figure 3).
Oxidative C-H insertion at C1 in 11 can generate either of
two isomeric η3-Ir(III) complexes, 12 or 13. Isomerization
of these intermediates to the corresponding η1 complexes 9
and 10 must precede reductive elimination of the vinyl ether.
Destabilization of 10 due to the A1,3 interaction incurred
homoallyl ether 14 participated in stereoselective tandem
olefin isomerization to the corresponding (E,Z)-allyl vinyl
ether and in situ [3,3] sigmatropic rearrangement to afford
the 2,3-anti-pentenal derivative 15 (81% ee).
Ring-bearing Claisen substrates often exhibit attenuated
diastereoselection due to limited energetic differentiation of
the competing boat and chair transition states.13 The cyclo-
hexenol-derived di(allyl) ethers 16a and 16b, therefore,
(10) (a) Kim, H.; Lee, C. Org. Lett. 2002, 4, 4369-4371. (b) Stevens,
B. D.; Nelson, S. G. J. Org. Chem. 2005, 70, 4375-4379. (c) Ref 6b.
(11) Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla,
U. S. J. Am. Chem. Soc. 1990, 112, 2389-2392.
(12) The enantioselectivity obtained in preparing 14 was not optimized.
Org. Lett., Vol. 9, No. 12, 2007
2327

provided an especially stringent test for the stereocontrol
available from the ICR-based Claisen rearrangements. At-
tempted ICR reorganization of these substrates under typical
thermal reaction conditions afforded poor conversion or
decomposition at more elevated temperatures (eq 3). Alter-
to be an equally efficient Lewis acid promoter, generating
the neopentyl alcohols 18a/b as single diastereomers (71 and
62% yield, respectively), thereby affording direct entry to
alcohol-containing Claisen adducts without resorting to a
separate aldehyde reduction step.15
Olefin isomerization-Claisen rearrangement reactions
provide convenient access to stereodefined all-carbon
stereocenters and vicinal quaternary-tertiary stereocenter
relationships. The success of these reactions enables a variety
of easily accessed strategies for achieving enantioselective
quaternary carbon installation.
Acknowledgment. Support from the National Science
Foundation (CHE 0316000), the National Institutes of Health
(P50 GM067082) for the University of Pittsburgh Center for
Chemical Methodologies and Library Development
(UPCMLD), the Bristol-Myers Squibb Foundation, and the
Merck Research Laboratories is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and representative 1H and 13C spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
natively, following Ir(I)-catalyzed isomerization, reacting the
crude allyl vinyl ether with Me2AlCl (1.0 equiv, -40 °C)
afforded the Claisen-derived aldehyde 17 as a single di-
astereomer (57% yield).14 Diisobutylaluminum hydride proved
OL0706511
(14) Tayama, E.; Saito, A.; Ooi, T.; Maruoka, K. Tetrahedron 2002, 58,
8307-8312 and references therein.
(15) For the use of diisobutylaluminum hydride as a promoter for Claisen
rearrangements, see ref 6a.
(13) (a) Ireland, R. E.; Daub, J. P. J. Org. Chem. 1981, 46, 479-485.
(b) Bartlett, P. A.; Pizzo, C. F. J. Org. Chem. 1981, 46, 3896-3900.
2328
Org. Lett., Vol. 9, No. 12, 2007